Chronic pain is a major public health challenge that is inadequately addressed. The neural substrate of chronic pain includes disruption of numerous central nervous system (CNS) processes, and depression is a common consequence of chronic pain. The medial prefrontal cortex (mPFC) is a key brain area that regulates depres- sion, and the development of depression has been linked to disrupted synaptic function in the mPFC involving signaling through the endocannabinoid (eCB) system. Additionally, anatomical and electrophysiological studies show that afferent nociceptive pathways connect to the mPFC. We hypothesize that acute pain initially induces excess CB1R activation that eventually leads to CB1R downregulation, resulting in elevated GABAergic inner- vation of mPFC pyramidal neurons that persists as a chronic phase of reduced mPFC activity, with the final result being behavioral depression. This hypothesis is supported by preliminary data that reveal increased ac- tivity of mPFC pyramidal neurons and elevated 2-arachidonoylglycerol during the acute phase of nerve injury pain, and chronically desensitized CB1Rs that results in deactivation of mPFC pyramidal neurons, and deacti- vation of mPFC pyramidal neurons that cause depression-like behavior in animals. The proposed experiments will substantiate these promising findings, probe mechanistic details, and explore possible therapies. Specifi- cally, Aim 1 experiments will identify time courses of eCB signaling, mPFC activity, and depression-like behav- ior at early and late phases of neuropathic pain. Aim 2 will examine the state of mPFC synaptic function after initiation of pain and the causal linkage between eCB levels and synaptic function under these conditions. Fi- nally, Aim 3 will use diverse approaches to modulate this signaling pathway in order to verify the mechanistic findings of Aim 1 and 2, and to lay the groundwork for potential therapeutic strategies. Completion of the pro- posed project will not only generate new insights into the genesis of depression in neuropathic pain, but also may provide the proof-of-concept foundation for novel antidepressant treatments based on selective prevention or reversal of pain-induced CNS synaptic plasticity.